Substituted pyrazole compounds as crac modulators

Abstract

The present invention relates to compounds described herein Formula (I) and pharmaceutical acceptable salts thereof, which modulate the activity of calcium release-activated calcium (CRAC) channel. The invention also describes the compounds of Formula (I) and pharmaceutical compositions containing such compounds thereof for treating, managing, and/or lessening the severity of diseases, disorders, syndromes or conditions associated with the modulation of calcium release-activated calcium (CRAC) channel.

1 . A compound having the Formula (I): 
       
         
           
           
               
               
           
         
         wherein,
 one of A and B is N and the other is CR 3 ; 
 L is selected from —C(O)NR 11 —, —CR a R b NR 11 — and —NR 11 CR a R b —; 
 at each occurrence, R a  and R b  are independently hydrogen, substituted or unsubstituted alkyl or halogen; 
 ring E is 5 membered non aromatic heterocyclic ring selected from Formula (a) to (c) 
 
       
       
         
           
           
               
               
           
         
         
           at each occurrence, X is selected from —C(O)—, —CR 4 R 5 — and —NR—; 
           at each occurrence, Y is —C(O)— or —CR 4 R 5 —; 
           provided that both of X and Y are not simultaneously —C(O)—; 
           R is selected from substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, —C(O)NR 6 R 7 , —C(O)OR 9  and —C(O)R 8 ; 
           R 1 , which may be same or different at each occurrence, is independently selected from halogen, cyano, nitro, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkoxy, —NR 6 R 7 , —NHC(O)R 8 , and —C(O)OR 9 ; or any two of adjacent R 1  groups together with the phenyl to which they are attached form substituted or unsubstituted naphthalene ring; 
           R 2  is selected from halogen, cyano, nitro, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkoxy, —NR 6 R 7 , —NHC(O)R 8 , and —C(O)OR 9 ; 
           R 3  is selected from hydrogen, halogen, cyano, nitro, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkoxy, —NR 6 R 7 , —NHC(O)R 8 , and —C(O)OR 9 ; 
           R 4  and R 5 , which may be same or different at each occurrence, are independently selected from hydrogen, halogen, —OR 10 , substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted hydroxyalkyl, —C(O)OR 9 , —C(O)—NR 6 R 7 , substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocyclyl; provided that, when any of R 4  or R 5  in Y is —OR 10  then R 10  is not hydrogen; 
           R 6  and R 7 , which may be same or different at each occurrence, are independently selected from hydrogen, substituted or unsubstituted alkyl and substituted or unsubstituted cycloalkyl; or R 6  and R 7 , together with the nitrogen atom to which they are attached, may form a substituted or unsubstituted, saturated or unsaturated 3 to 12 membered cyclic ring, wherein the unsaturated cyclic ring may have one or two double bonds; 
           R 8 , which may be same or different at each occurrence, is independently selected from substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted aryl; 
           R 9 , which may be same or different at each occurrence, is independently selected from hydrogen, substituted or unsubstituted alkyl and substituted or unsubstituted aryl; 
           R 10  is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocyclyl; 
           at each occurrence, R 11  is independently hydrogen or substituted or unsubstituted alkyl; and 
           n is an integer ranging from 0 to 4, both inclusive; 
           or a pharmaceutically acceptable salt thereof. 
         
       
     
     
         2 . The compound of  claim 1 , having the Formula (II): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof; 
         wherein ring E, R 1 , R 2 , R 3 , L and ‘n’ are as defined in claim- 1 . 
       
     
     
         3 . The compound of  claim 1 , having the Formula-(III): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof; 
         wherein ring E, R 1 , R 2 , R 3 , L and ‘n’ are as defined in claim- 1 . 
       
     
     
         4 . The compound of  claim 1 , wherein ring E is selected from (a) to (c) 
       
         
           
           
               
               
           
         
         wherein R, X and Y as defined in claim- 1 , and or a pharmaceutically acceptable salt thereof. 
       
     
     
         5 . The compound of  claim 1 , wherein L is selected from —C(O)NR 11 —, —NR 11 C(O)— and —NR 11 CR a R b — wherein R 11 , R a  and R b  are independently a hydrogen or substituted or unsubstituted alkyl. 
     
     
         6 . The compound of  claim 1 , wherein R 1  is same or different and are independently selected from halogen, cyano, nitro, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy and substituted or unsubstituted cycloalkyl; and ‘n’ is 0, 1, 2, or 3. 
     
     
         7 . The compound of  claim 1 , wherein R 2  is selected from halogen, hydroxyl, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy and substituted or unsubstituted cycloalkyl. 
     
     
         8 . The compound of  claim 1 , wherein R 3  is selected from hydrogen, halogen, cyano, nitro, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkoxy and substituted or unsubstituted cycloalkyl. 
     
     
         9 . The compound of  claim 1 , wherein one of A and B is N and the other is CH; L is —C(O)NH—, —NHC(O)— or —NHCH 2 —; R 1  is same or different and are independently selected from halogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl and substituted or unsubstituted cycloalkyl; ‘n’ is 0, 1, 2, or 3; R 2  is halogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl or substituted or unsubstituted cycloalkyl; R 3  is selected from hydrogen, halogen or substituted or unsubstituted alkyl; and ring E is selected from 
       
         
           
           
               
               
           
         
       
     
     
         10 . The compound of  claim 1 , which is selected from:
 2,6-Difluoro-N-(6-(5-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)benzamide;   2-Fluoro-6-methyl-N-(6-(5-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)benzamide;   5-(3-Cyclopropyl-1-(5-((2,6-difluorobenzyl)amino)pyridin-2-yl)-1H-pyrazol-5-yl)-3-methyl-1,3,4-oxadiazol-2(3H)-one;   N-(6-(3-(Difluoromethyl)-5-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,6-difluorobenzamide;   5-(1-(5-((2,6-Difluorobenzyl)amino)pyridin-2-yl)-5-(fluoromethyl)-1H-pyrazol-3-yl)-3-methyl-1,3,4-oxadiazol-2(3H)-one;   Methyl 3-(1-(5-((2,6-difluorobenzyl)amino)pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)-5-methyl-4,5-dihydroisoxazole-5-carboxylate;   Methyl 3-(1-(5-((2-chloro-6-fluorobenzyl)amino)pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)-5-methyl-4,5-dihydroisoxazole-5-carboxylate;   2,6-Difluoro-N-(6-(3-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)benzamide;   2-Chloro-6-fluoro-N-(6-(3-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)benzamide;   2-Fluoro-6-methyl-N-(6-(3-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)benzamide;   N-(6-(5-(Difluoromethyl)-3-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,6-difluorobenzamide;   5-(1-(5-((2,6-Difluorobenzyl)amino)pyridin-2-yl)-5-(difluoromethyl)-1H-pyrazol-3-yl)-3-methyl-1,3,4-oxadiazol-2(3H)-one;   5-(1-(5-((2,6-Difluorobenzyl)amino)pyridin-2-yl)-3-(difluoromethyl)-1H-pyrazol-5-yl)-3-methyl-1,3,4-oxadiazol-2(3H)-one;   N-(6-(3-(5,5-Dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,6-difluorobenzamide;   2-Chloro-N-(6-(3-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)-6-fluorobenzamide;   2,6-Difluoro-N-(6-(1′,4′,4′-trimethyl-5′-oxo-5-(trifluoromethyl)-4′,5′-dihydro-1H,1′H-[3,3′-bipyrazol]-1-yl)pyridin-3-yl)benzamide;   2-Chloro-6-fluoro-N-(6-(1′,4′,4′-trimethyl-5′-oxo-5-(trifluoromethyl)-4′,5′-dihydro-1H,1′H-[3,3′-bipyrazol]-1-yl)pyridin-3-yl)benzamide;   2-Fluoro-6-methyl-N-(6-(1′,4′,4′-trimethyl-5′-oxo-5-(trifluoromethyl)-4′,5′-dihydro-1H,1′H-[3,3′-bipyrazol]-1-yl)pyridin-3-yl)benzamide;   2,6-Difluoro-N-(6-(3-(4-methyl-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)benzamide;   N-(6-(3-(4-Acetyl-5,5-dimethyl-4,5-dihydro-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,6-difluorobenzamide;   N-(6-(3-(4,4-Dimethyl-4,5-dihydrooxazol-2-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,6-difluorobenzamide;   5-(1-(5-((2,6-Difluorobenzyl)amino)pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)-3-methyl-1,3,4-oxadiazol-2(3H)-one;   5-(1-(5-((2-Chloro-6-fluorobenzyl)amino)pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)-3-methyl-1,3,4-oxadiazol-2(3H)-one;   1′-(5-(2,6-Difluorobenzyl)amino)pyridin-2-yl)-1,4,4-trimethyl-5′-(trifluoromethyl)-1H,1′H-[3,3′-bipyrazol]-5(4H)-one;   1′-(5-((2-Chloro-6-fluorobenzyl)amino)pyridin-2-yl)-1,4,4-trimethyl-5 (trifluoromethyl)-1H, 1′H-[3,3′-bipyrazol]-5(4H)-one;   3-(1-(5-((2,6-Difluorobenzyl)amino)pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)-4-methyl-1,2,4-oxadiazol-5(4H)-one;   1-(5-(1-(5-((2,6-Difluorobenzyl)amino)pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)-2,2-dimethyl-1,3,4-oxadiazol-3 (2H)-yl)ethanone;   N-(2,6-Difluorobenzyl)-6-(3-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-amine;   N-(6-(5-Cyclopropyl-3-(4-methyl-5-oxo-4, 5-dihydro-1,3,4-oxadiazol-2-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,6-difluorobenzamide;   N-(6-(3-Cyclopropyl-5-(4-methyl-5-oxo-4, 5-dihydro-1,3,4-oxadiazol-2-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,6-difluorobenzamide;   2,6-Difluoro-N-(6-(5-methyl-3-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-1H-pyrazol-1-yl)pyridin-3-yl)benzamide;   5-(1-(5-((2,6-Difluorobenzyl)amino)pyridin-2-yl)-5-methyl-1H-pyrazol-3-yl)-3-methyl-1,3,4-oxadiazol-2(3H)-one;   (3-(1-(5-((2,6-Difluorobenzyl)amino)pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)-5-methyl-4,5-dihydroisoxazol-5-yl)methanol;   (3-(1-(5-((2-Chloro-6-fluorobenzyl)amino)pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)-5-methyl-4,5-dihydroisoxazol-5-yl)methanol;   Methyl 3-(1-(5-(2,6-difluorobenzamido)pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)-5-methyl-4,5-dihydroisoxazole-5-carboxylate;   2,6-Difluoro-N-(6-(3-(5-(hydroxymethyl)-5-methyl-4,5-dihydroisoxazol-3-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)benzamide;   3-(1-(5-(2, 6-Difluorobenzamido)pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)-5-methyl-4, 5-dihydroisoxazole-5-carboxamide;   2, 6-Difluoro-N-(5-(3-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-2-yl)benzamide;   2-Chloro-6-fluoro-N-(5-(3-(4-methyl-5-oxo-4, 5-dihydro-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-2-yl)benzamide;   2-Fluoro-6-methyl-N-(5-(3-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-2-yl)benzamide;   2-Fluoro-N-(5-(3-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-2-yl)benzamide;   2,3-Difluoro-N-(5-(3-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-2-yl)benzamide;   2,4,5-Trifluoro-N-(5-(3-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-2-yl)benzamide;   2,3,4-Trifluoro-N-(5-(3-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-2-yl)benzamide;   2,4-Difluoro-N-(5-(3-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-2-yl)benzamide;   2,3-Dimethyl-N-(5-(3-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-2-yl)benzamide;   2-Chloro-N-(5-(3-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-2-yl)benzamide;   2-Methyl-N-(5-(3-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-2-yl)benzamide;   4-Ethyl-N-(5-(3-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-2-yl)benzamide;   N-(5-(3-(4-Methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-2-yl)-2-naphthamide;   5-(1-(6-((2,6-Difluorobenzyl)amino)pyridin-3-yl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)-3-methyl-1,3,4-oxadiazol-2(3H)-one;   5-(1-(6-((2-Chloro-6-fluorobenzyl)amino)pyridin-3-yl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)-3-methyl-1,3,4-oxadiazol-2(3H)-one;   5-(1-(6-((2-Fluoro-6-methylbenzyl)amino)pyridin-3-yl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)-3-methyl-1,3,4-oxadiazol-2(3H)-one;   N-(2,6-Difluorophenyl)-6-(3-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)nicotinamide and   N-(2-Chloro-6-fluorophenyl)-6-(3-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)nicotinamide   or pharmaceutically acceptable salt thereof.   
     
     
         11 . A pharmaceutical composition comprising one or more compounds of Formula (I) according to  claim 1  and one or more pharmaceutically acceptable excipients. 
     
     
         12 . A method of treating, managing and/or lessening diseases or disorders, syndromes or conditions associated with the modulation of calcium release-activated calcium (CRAC) channel in a subject in need thereof wherein the method comprises administering to the subject a therapeutically effective amount of a compound of  claim 1  or a pharmaceutically acceptable salt thereof. 
     
     
         13 . The method of  claim 12 , wherein the diseases, disorders, syndromes or conditions associated with the modulation of calcium release-activated calcium (CRAC) channel are selected from the group consisting of inflammatory diseases, autoimmune diseases, allergic disorders, organ transplant, cancer and cardiovascular disorders. 
     
     
         14 . The method of  claim 12 , wherein the disease is rheumatoid arthritis, multiple sclerosis and psoriasis. 
     
     
         15 . The method of  claim 12 , wherein the disease is allergic disorders selected from asthma, chronic obstructive pulmonary disorder (COPD) or respiratory disorders. 
     
     
         16 . The method of  claim 13 , wherein inflammatory diseases are selected from rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, psoriatic arthritis, chronic obstructive pulmonary disease (COPD), inflammatory bowel diseases, pancreatitis, peripheral neuropathy, multiple sclerosis (MS) and inflammation associated with cancer. 
     
     
         17 . A process for the preparation of a compound of Formula (IIa): 
       
         
           
           
               
               
           
         
         wherein L is —NR 11 C(O)— or NR 11 CR a R b ; 
         ring E, A, B, R a , R b , R 1 , R 2 , R 3 , R 11  and ‘n’ are as described herein above; 
         the process comprising the steps: 
         a) oxidizing a compound of Formula (10) where X is halogen, NO 2 , COOR′ where R′ is H, alkyl etc., by using suitable oxidation agents to give compound of Formula (11) in suitable solvent(s); 
       
       
         
           
           
               
               
           
         
         b) converting a acid compound of Formula (11) to cyclized compound of compound of Formula (12) by following acid ester formation then heterocyclic ring formation using hydrazine hydrate followed by triphosgene 
       
       
         
           
           
               
               
           
         
         c) coupling of compound Formula (12) where X′ is halogen, with compound of Formula (6) where L′ is C(O) or CR a R b  where R a , R b  and R 11  are hydrogen or alkyl, to give compound of Formula (IIa) by using suitable reagents and suitable solvent. 
       
       
         
           
           
               
               
           
         
       
     
     
         18 . The process for the preparation of compound  claim 17 , having the Formula (IIa): 
       
         
           
           
               
               
           
         
         wherein L is —NR 11 C(O)— or NR 11 CR a R b ; 
         ring E, A, B, R a , R b , R 1 , R 2 , R 3 , R 11  and ‘n’ are as described herein above; 
         the process comprising the steps: 
         a) reducing a nitro group in compound of Formula (12) where X′ is NO 2 , by using suitable reducing agent to give amino compound of Formula (13) where R 11  is hydrogen, in suitable solvent 
       
       
         
           
           
               
               
           
         
         b) coupling of compound of Formula (13) with compound of Formula (8) by using suitable amide coupling reagents or suitable reductive amidation reagents to give compound of Formula (IIa) 
       
       
         
           
           
               
               
           
         
       
     
     
         19 . A process for the preparation of a compound of Formula (IIb): 
       
         
           
           
               
               
           
         
         wherein ring E, A, B, R 1 , R 2 , R 3 , R 11  and ‘n’ are as described herein above; 
         amide coupling of compound Formula (12) where X′ is COOR′ where R′ is H, alkyl etc., with compound of Formula (5a) to give compound of Formula (IIb) by using suitable amide coupling methods